One-step preparation of drug-containing microparticles to enhance the dissolution and absorption of poorly water-soluble drugs using a 4-fluid nozzle spray drier

We studied the use of a 4-fluid nozzle spray drier as a new one-step method for preparing drug-containing microparticles to enhance the dissolution and absorption of poorly water-soluble drugs. We employed ethenzamide (EZ) and flurbiprofen (FP) as poorly water-soluble drugs and lactose (LAC) and mannitol (MAN) as water-soluble carriers for microparticles. EZ-ethanol or FP-acetone/methanol (2:1) solutions and aqueous solutions of LAC or MAN were simultaneously supplied through different liquid passages of a 4-fluid nozzle spray drier and then dried to obtain LAC or MAN microparticles containing EZ or FP. The dissolution of EZ from the EZ/LAC and EZ/MAN microparticles was much faster than that from EZ powder. The dissolution of EZ was more rapid from the EZ/MAN microparticles than the EZ/LAC microparticles. The dissolution of FP from the FP/MAN microparticles was greatly enhanced because of large effective surface area of FP dispersed in microparticles following rapid dissolution of MAN. The absorption of FP after oral administration of the FP/MAN microparticles to rats was markedly increased. The results demonstrate that the 4-fluid nozzle spray drier can be used for the one-step preparation of drug-containing microparticles that enhance the dissolution and absorption of poorly water-soluble drugs and that overcome the problem of finding a common solvent for drugs and carriers.     

Early use of a mechanical stretching device to improve mandibular mobility after composite resection: a pilot study

OBJECTIVE: To evaluate the use of a mechanical stretching device, the Therabite, for the early postoperative management of trismus in select patients. DESIGN: Prospective series of consecutive head and neck cancer patients. SETTING: Academic, tertiary referral center. PARTICIPANTS: Seven patients with oropharyngeal carcinoma who underwent resection and radial forearm flap reconstruction. Five had midline mandibulotomy procedures for exposure. Six had radiation therapy (2 pre, 4 post). INTERVENTIONS: Patients were given a Therabite mechanical jaw mobilization device, were instructed in its proper use, and began using it within 6 weeks postoperatively. MAIN OUTCOME MEASURES: Maximal interincisor opening (MIO) was measured at the beginning of use and at the most recent postoperative visit. A 5-question self-assessment telephone survey was administered on study completion. RESULTS: The average MIO was 30 mm (range, 21-38 mm) at the beginning of the study and 40 mm (range, 30-57 mm) at the last visit. Average gain in MIO was 10 mm (range, 1-21 mm). Four of 5 assessable patients had minimal or no limitation on overall quality of life relative to jaw opening. No complications were associated with use of the device. Two patients could not be located for follow-up. CONCLUSIONS: The Therabite mechanical stretching device is effective and safe for the management of trismus in a select group of head and neck cancer patients after extensive ablation and complex reconstruction. Specifically, there were no adverse effects in the 5 patients who had undergone midline mandibulotomy.     

A model for the drug release from a polymer matrix tablet--effects of swelling and dissolution.

A model for simulating the drug release from a swelling and dissolving polymer tablet is presented and verified to data. The model is based on a mechanistic approach, and it can therefore be employed to study the sensitivity of true physical constants, for instance the drug diffusion coefficient or the drug solubility. The model generates the drug and polymer release profiles and the front positions of the total tablet, the solid core, and of the solid-drug-solubilized-drug interface. The convective contribution to mass transfer is shown to be of great importance. This is most markedly noticed for slowly diffusing drugs. In a simulation with a low value of the drug diffusion coefficient, it is shown that the initial drug release rate is faster than the polymer dissolution rate, followed by a second stage with a slower drug release rate. Furthermore, it is shown that polymer dissolution influences the drug release profile significantly, but not the front position of saturated drug in the gel layer. The model is verified against drug release and polymer dissolution data for the slightly soluble drug Methyl paraben and the soluble drug Saligenin in a poly (ethylene oxide) tablet, resulting in good agreement between model and experiments.     

The use of a daily goals sheet to improve communication in the paediatric intensive care unit.

OBJECTIVE: To assess the impact of the implementation of a daily goals sheet upon nursing perception of communication in an academic, tertiary care paediatric intensive care unit (PICU). DESIGN: Prospective, longitudinal, before-and-after intervention surveys. SETTING: University affiliated 12-bed PICU. SUBJECTS: Bedside nurses. INTERVENTIONS: A questionnaire was administered to PICU nurses addressing their perception of communication. Following this questionnaire, the use of a daily goals sheet was instituted. A second questionnaire was administered one year later. Mann-Whitney Rank Sum Test was used to compare differences of the graded outcome variables. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the perception of communication taken from a nursing perspective. Eighty-five percent of nurses felt the daily goals sheet led to improved communication between physicians and nurses in the PICU. All questions related to communication demonstrated a positive influence of the goals sheet, with the perception of the PICU staff working as a team reaching statistical significance (p=0.05). The perception of the care of one surgical service being attending physician directed also significantly improved after the institution of the goals sheet (p=0.04). CONCLUSION: The institution of a daily goals sheet led to an improvement in nursing perception of communication. Future studies are required to determine if this change in process has a demonstrable effect on health care outcomes of critically ill children, or whether this tool can have the same beneficial effects in other academic and non-academic PICUs.     

Chronic venous insufficiency in persons with a history of injection drug use.

Persons with a history of injection drug use have many risk factors for the development of chronic venous insufficiency (CVI), yet this phenomenon has not been studied systematically in this population. Persons (N = 204) with a history of injection drug use who were in enrolled in a treatment center were examined for clinical manifestations of CVI. The CVI clinical classification was graded on a 7-point scale for each leg. Most participants (n = 179, 87.7%) exhibited clinical evidence of CVI. Significant predictors of CVI clinical manifestations were leg infections/cellulitis (rho =.53); years injection in the veins of the groin, legs, and feet (rho =.47); deep vein thrombosis (rho =.37); and total years injection heroin (rho =.27). There was a linear functional relationship between years of injection drug use and the CVI clinical classification, but only when the injections were in the veins of the groin, legs, or feet; otherwise, the specific mechanisms of this relationship were not evident. The findings indicate that CVI is a common occurrence in persons who have injected drugs.     

Screening for drug abuse: use of NaCl to increase drug recovery from papers coated with ion-exchange resin.

Use of papers loaded with ion-exchange resins to adsorb drugs from urine specimens resulted in large losses during the procedure. The first step, removal of drugs from urine specimens, was 25-85% efficient. The second step, elution of drugs from paper for further processing, was approximately 40-70% complete. The efficiency of the first step was decreased and the efficiency of the second step was increased by addition of NaCl, except in the case of barbiturates. Presence of salt during elution increased the yield of dihydromorphine by 20%, of methadone by 16%, of amphetamine by 34%, and of chlorpromazine by 40%, but did not enhance the yield of pentobarbital. Overall recovery rates were: 51% for the opiates, 57% for methadone, 72% for a phenothiazine tranquillizer, but only 35% for amphetamine and 15% for a barbiturate.     

A protocol to improve analgesia use in the accident and emergency department.

OBJECTIVE--To assess the use of analgesia in an accident and emergency (A&E) department and identify shortcomings. SETTING--University teaching hospital. METHODS--An audit of patients referred from the A&E department to orthopaedic fracture clinic (n = 100) or for orthopaedic admission (n = 100) was carried out to document analgesia use. An analgesia protocol was introduced and analgesia use was reassessed on the same numbers of patients. RESULTS--Prescribing of analgesia was initially poor: 91% of fracture clinic referrals and 39% of admissions received no analgesia while in the A&E department; when given, it was often by inappropriate routes. Introduction of an analgesia protocol significantly improved analgesia use: fracture clinic referrals receiving unsatisfactory analgesia were reduced from 91% to 69% (P < 0.001). There was a marked increase in the use of intravenous analgesia, from 9% to 37% (P < 0.001). CONCLUSIONS--Large numbers of patients still receive no analgesia while in the A&E department. This seems to be a common problem requiring intervention at a national level. The absence of a coordinated approach to improving analgesia provision for acute trauma in the United Kingdom should be addressed urgently.     

Formation of drug-arylsulfonate complexes inside liposomes: a novel approach to improve drug retention.

The development of procedures to enhance drug retention in liposomes is important in order to achieve therapeutically optimized rates of drug release from liposomal carriers. In this study, the ability of lipophilic weak base drugs to complex with arylsulfonates resulting in formation of intravesicular precipitates is investigated as a means to enhance drug retention. It is shown that the arylsulfonates benzenesulfonate and hydroxybenzenesulfonate (HBS) induce precipitation of ciprofloxacin and vinorelbine, two representative weak base drugs that are difficult to retain in liposomal systems. The most complete precipitation was observed at pH values corresponding to charge neutralization of the drug-arylsulfonate complex. HBS is shown to be a much more effective precipitating agent than benzenesulfonate. It is also shown that vinorelbine and ciprofloxacin can be loaded into large unilamellar vesicles (LUV) containing the calcium salt of HBS using an ionophore-based loading method. Following drug loading, the formation of intravesicular drug-arylsulfonate precipitates of vinorelbine and ciprofloxacin was observed by cryo-electron microscopy. In vitro release experiments showed substantial improvements in drug retention for both vinorelbine and ciprofloxacin when HBS was present as compared to standard loading procedures employing MgSO4 as the entrapped solute. In vivo release experiments for vinorelbine in NuNu mice indicated a half-time for release for HBS-containing LUV of approximately 30 h, compared to 6.4 h for LUV loaded employing MgSO4. It is suggested that encapsulation procedures employing HBS in the internal medium can improve the retention of drugs that are difficult to retain in liposomes, possibly leading to enhanced therapeutic properties.     

Topical application of acyclovir-loaded microparticles: quantification of the drug in porcine skin layers.

The goal of this work was to increase the amount of acyclovir (ACV) in the basal epidermis, site of Herpes virus simplex infections, using microparticles as carriers. Poly(D,L-lactic-co-glycolic acid) microparticles loaded with ACV were prepared using a solvent evaporation technique. ACV distribution into porcine skin after topical application of microparticles for 6, 24 and 88 h, was determined by horizontal slicing of the skin. An ACV suspension served for comparison. The results showed that, at 6 and 24 h, the quantity of the drug in the basal epidermis with the microparticles, is similar to that obtained with the ACV suspension. However, after 88 h, the ACV reservoir in the basal epidermis was higher with the microparticles compared with the control suspension. This could be explained by the controlled drug release produced by the vector in the basal epidermis. Besides, at 88 h the amount of ACV detected in the receptor chamber of the diffusion cells was much lower with the microparticles than with the suspension. This type of carrier can improve acyclovir topical therapy since it increases drug retention in the basal epidermis and consequently increases the time intervals between doses.     

Subcutaneous drug administration. Indications for the use in terminal patients

The preferred methods to administer medicines to the sick are oral, under the tongue, or rectal; but in the case of the terminally ill patient, we may encounter the problem that the drugs which they tend to require do not come in either of these preferred administering methods since these patients symptoms and problems demand complex responses. In these cases, the subcutaneous way winds up being highly recommended; therefore, the authors present the pharmacological bases of this method, they describe continuous subcutaneous perfusion, and all those aspects of this method which might be interesting to the professionals who employ it.     

The use of a template to improve the management of distal radial fractures

Objectives: The aim of this study was to reduce the number of inappropriately managed distal radial fractures with the use of a template. Methods: A template has been developed to aid junior doctors and emergency nurse practitioners (ENPs) to decide which distal radial fractures require manipulation. Emergency Department (ED) junior doctors and ENPs were asked to review the radiographs of 12 distal radial fractures with and without the template and comment on whether the fracture required manipulation. Results: There was an improvement in appropriate management with the template of 16.6% for the junior doctors and 22.3% for the ENPs. This was statistically significant for both groups when the results were analysed with a paired t test (p<0.01). Conclusions: We conclude that the availability of this template in the ED may be helpful to junior doctors and ENPs, and represents a low cost and efficient way of reducing the number of patients who attend a fracture clinic with a distal radial fracture in an unsatisfactory position. This may also reduce the numbers requiring admission and a manipulation under anaesthetic, which spares the patients the risks of general anaesthesia and may possibly be cost saving.     

The delivery of aerosolized steroids from MDIs with nozzle extensions: Quantitative laboratory evaluation of a method to improve aerosol delivery to intubated patients

Objective Pulmonary deposition of aerosolized drug from a metered dose inhaler (MDI) is low with intubated patients. In the laboratory, extension of the MDI nozzle to the endotracheal tube tip has been shown to increase the delivered dose of albuterol. The objectives of this study were to determine the dose of aerosolized steroid (beclomethasone and triamcinolone) delivered through a MDI nozzle extension, the effect of nozzle extension length and number of actuations on the delivered dose, and particle size delivered through the nozzle extension.Design A 19-G catheter was used as the MDI nozzle extension. The nozzle extension was attached to a 60-ml syringe via the Luer-Lok connection, and the distal end was directed through a hole drilled into a 15-ml capped tube. The MDI was placed into the syringe and actuated by pressing the syringe plunger. Drug delivered through the nozzle extension into the tube was dissolved in methanol (beclomethasone) or ethanol (triamcinolone). Nozzle extension lengths of 10 cm, 20 cm and 30 cm were studied. For each nozzle extension length, delivery was assessed using one, two, three and five actuations of each drug. Drug remaining in the nozzle extension was recovered by rinsing with the appropriate solvent. Aerosol particle size leaving the nozzle extension was determined using a seven-stage cascade impactor. Beclomethasone and triamcinolone concentrations were determined by spectrophotometry at 239 nm.Setting Respiratory care laboratory of a university teaching hospital.Results For the pooled results, 70.2±14.1% of the dose was delivered through the nozzle extension, with no difference between beclomethasone and triamcinolone (p=0.838). The proportion of drug delivered through the 10-cm extension (76.7±8.4%) was greater than that from the 20-cm (66.1±16.5%) and 30-cm (67.7±13.9%) extensions (p=0.001). Less drug was delivered through the extension with one actuation (54.1±17.7%) than with two (71.2±7.7%), three (77.2±5.5%), or five actuations (78.2±4.3%) (p<0.001). There was a decrease in MMAD with increasing nozzle extension length (3.14±0.61 m for 10 cm, 2.97±0.28 m for 20 cm, 2.37±0.27 m for 30 cm;p=0.005).Conclusions A high proportion of aerosolized steroid was delivered with a MDI actuated through a nozzle extension. The proportion delivered through the nozzle extension was significantly less with longer nozzle extensions and with fewer actuations, but this may not be clinically important. Although particle sizes were smaller from longer nozzle extensions, all were within the respirable range. These results suggest that steroids can be delivered efficiently using a MDI nozzle extension.Presented in part at the 1994 International Conference, ALA/ATS, in Boston, MA, May 23, 1994Work completed in the Respiratory Care Laboratory and Henry K. Beecher Anesthesia Laboratory, Massachusetts General Hospital, Boston, MA. Supported in part by the Puritan-Bennett Corporation and the American Respiratory Care Foundation     

Successful use of sodium ferric gluconate in sucrose in a patient with multiple drug allergies.

This is not a controlled study but an anecdotal experience that resulted in improved outcomes in a patient with multiple allergies, including iron dextran. Target Hct/Hgbs were attained and exceeded, although iron indices were not fully achieved. Infections demonstrated RE blockade and failure of TSAT to reach target range. The multidisciplinary team's successful decision to trial SFG in a medically complex patient allowed profound iron deficiency to be treated safely and effectively, which was not possible prior to the availability of an alternate iron preparation. It is rewarding to have the option to offer a medication that improves patients' status and enhances outcomes. Mr. C. was less tired and had more energy following his first and subsequent courses of therapy. "I couldn't believe how tired I was without realizing it until after I finished a course of iron therapy. I just thought that was my quality of life on dialysis. It's much better now and I have more energy." Such comments justify our efforts on our patients' behalf.     

A multi-intervention approach on drug therapy can lead to a more appropriate drug use in the elderly. LIMM-Landskrona Integrated Medicines Management

Rationale, aims and objectives  To evaluate if an integrated medicines management can lead to a more appropriate drug use in elderly inpatients.
Method  The study was an intervention study at a department of internal medicine in southern Sweden. During the intervention period pharmacists took part in the daily work at the wards. Systematic interventions aiming to identify, solve and prevent drug-related problems (DRPs) were performed during the patient's hospital stay by multidisciplinary teams consisting of physicians, nurses and pharmacists. DRPs identified by the pharmacist were put forward to the care team and discussed. Medication Appropriateness Index (MAI) was used to evaluate the appropriateness in the patients' drug treatment at admission, discharge and 2 weeks after discharge. In total 43 patients were included, 28 patients in the intervention group and 25 patients in the group which was used as control.
Results  For the intervention group there was a significant decrease in the number of inappropriate drugs compared with the control group ( P  = 0.049). Indication, duration and expenses were the MAI-dimensions with most inappropriate ratings, and the drugs with most inappropriate ratings were anxiolytics, hypnotics and sedatives.
Conclusion  This kind of systematic approach on drug therapy can result in a more appropriate drug use in the elderly.     

Utility of a composite measure to detect problematic alcohol use in persons with traumatic brain injury

OBJECTIVES: To examine factors complicating the study of alcohol-related effects in traumatic brain injury (TBI) patients and to evaluate a composite measure to categorize such patients according to degree of alcohol-related problems. DESIGN: Inception cohort. SETTING: Level I trauma center. PATIENTS: Consecutively hospitalized adult TBI patients (n = 156; 73% men; 87% Caucasian; mean age, 30yr; mean education, 12yr). Selection criteria required objective evidence of brain trauma; minimum survival of 1 month postinjury; age 15 years or older; and English speaking. MAIN OUTCOME MEASURES: An index of problematic drinking based on a measure created by combining blood-alcohol level, quantity-frequency of consumption, and the Short Michigan Alcoholism Screening Test. Preinjury characteristics were obtained through structured interview. RESULTS: Participants with highly problematic drinking showed poorer premorbid psychosocial functioning, including lower educational attainment, greater likelihood of problems with the law, lower perceived social support, and greater prevalence of other substance abuse. CONCLUSION: The composite index is useful in identifying problematic drinkers among TBI patients. Results have implications for interpreting and planning research on the role of alcohol in TBI outcomes.